[Federal Register: August 18, 2004 (Volume 69, Number 159)]
[Rules and Regulations]               
[Page 51162-51171]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr18au04-3]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 514

[Docket No. 2000N-1399]

 
Presubmission Conferences

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing this final 
rule to amend its new animal drug regulations to implement a new 
provision of the Federal Food, Drug, and Cosmetic Act (the act). Under 
this new provision of the act, as amended by the Animal Drug 
Availability Act of 1996 (ADAA), any person intending to file a new 
animal drug application (NADA) or supplemental NADA or to investigate a 
new animal drug is entitled to one or more conferences with FDA to 
reach an agreement establishing a submission or investigational 
requirement. This final rule describes the procedures for requesting, 
conducting, and documenting such presubmission conferences.

DATES: This rule is effective November 1, 2004.

FOR FURTHER INFORMATION CONTACT: Gail Schmerfeld, Center for Veterinary 
Medicine (HFV-100), Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855, 301-827-1796, e-mail: gschmer1@cvm.fda.gov.

SUPPLEMENTARY INFORMATION:

I. Background

    Congress enacted the ADAA on October 9, 1996. Section 512(b)(3) of 
the act (21 U.S.C. 360b(b)(3)), as amended by the ADAA, provides that 
any person intending to file an NADA or supplemental NADA or to request 
an investigational exemption is entitled to one or more conferences 
with FDA prior to such submission to reach an agreement establishing a 
submission or investigational requirement. In the Federal Register of 
August 25, 2000 (65 FR 51782), we proposed amending the new animal drug 
applications regulations in part 514 (21 CFR part 514) to describe the 
procedures to be followed for requesting, conducting, and documenting 
presubmission conferences. Under the proposed rule and final rule, 
persons intending to file an abbreviated new animal drug application 
(ANADA) as well as persons intending to file an NADA or supplemental 
NADA are entitled to request presubmission conferences. FDA provided 75 
days for public comment on the proposed rule.

II. Comments on the Proposed Rule

    We received four letters from government, industry, and trade 
associations commenting on the proposed presubmission conference rule. 
Our response to the comments, grouped by codified section, follows.

A. General Comments

    (Comment 1) Two comments assert that presubmission conferences 
under section 512(b)(3) of the act represent a fundamental change in 
the manner the agency is to operate and a new way for the agency to do 
business.
    (Response) FDA disagrees with these comments. Presubmission 
conferences under 512(b)(3) of the act do not represent a fundamental 
change in the manner we operate. Although there was no statutory or 
regulatory entitlement to a presubmission conference prior to enactment 
of the ADAA, FDA's Center for Veterinary Medicine (CVM) had already 
been encouraging sponsors of NADAs to participate in conferences with 
us to discuss in detail what studies would be necessary to demonstrate 
the safety and effectiveness of particular new animal drugs being 
investigated. We found, as a result of this direct communication during 
the development and review of new animal drugs, that fewer unusable 
studies were conducted and there were fewer delays in the review 
process. Although such agreements were not legally binding, we 
attempted to be sensitive to industry's concern that we not change such 
requirements without justification. Our goal was to not change 
requirements unless we became aware of new information that suggested 
such requirements may no longer support approval.

B. Definitions (Sec.  514.3)

    In the proposed rule, the preamble discusses definitions in 
proposed Sec.  514.3. However, the Definitions section in the codified 
text in the proposed rule was mistakenly numbered Sec.  514.2. The 
definitions added by this final rule will be added to existing Sec.  
514.3 Definitions in alphabetical order.
    In the proposed rule, potential applicant was defined to mean any 
person intending to: (1) Investigate a new animal drug under section 
512(j) of the Federal Food, Drug, and Cosmetic Act (the act), (2) file 
a new animal drug application (NADA) or supplemental NADA under 
512(b)(1) of the act, or (3) file an abbreviated new animal drug

[[Page 51163]]

application (ANADA) under section 512(b)(2) of the act. Under Sec.  
514.5(c), a potential applicant may request one or more presubmission 
conferences prior to the filing of a NADA, supplemental NADA, or an 
ANADA. Thus, a person investigating a new animal drug under section 
512(j) of the act is also a potential applicant. We are revising the 
definition of ``potential applicant'' to include ``any person 
investigating a new animal drug under section 512(j).''
    In the proposed rule, the last sentence in the definition of 
presubmission conference agreement stated that ``The presubmission 
conference will be binding on the potential applicant and FDA unless it 
is modified as described in Sec.  514.4(g).'' We are deleting this 
sentence because it is unnecessary. As defined in the proposed and 
final rule, a presubmission conference is binding.
    (Comment 2) One comment expresses concern that the discussion in 
the preamble to the proposed rule appeared to limit presubmission 
conferences to just safety or effectiveness data generation.
    (Response) The specific statement that raised the concern appeared 
in the second section entitled ``Description of the Proposed Rule,'' 
``* * *. Meetings in which the focus is other than to establish the 
safety and effectiveness data requirement for new animal drugs (e.g.,* 
* *) are not specifically covered by this proposed rule'' (65 FR 51782 
at 51783).
    We did not intend that statement to be read to limit which meetings 
will be considered presubmission conferences. Most, if not all, 
investigational and submission requirements relate to establishing 
safety or effectiveness data requirements.
    The key factor in determining whether a meeting is a presubmission 
conference is, as implied in section 512(b) of the act and the 
definition of presubmission conference in Sec.  514.3(b), whether such 
meeting is ``* * * to reach a binding agreement establishing a 
submission or investigational requirement.'' Generally, the goal of a 
presubmission conference is to reach agreement on some or all of the 
investigational or submission requirements for a particular new animal 
drug. But, so long as the intent of a meeting is to discuss 
investigational or submission requirements, it is a presubmission 
conference even if the parties are unable to reach agreement.
    However, there may be some meetings that are not related to the 
establishment of investigational or submission requirements that will 
not be covered by this regulation because they are not presubmission 
conferences. For example, a meeting requested by a company to present 
information about all of its ongoing research and development projects 
would not be a presubmission conference. Furthermore, a meeting to 
discuss a pending submission would not be a presubmission conference. 
As the term ``presubmission'' implies, submission requirements should 
be discussed before we receive a submission. Meetings to discuss 
pending submissions could give potential applicants an unfair advantage 
because they could have the effect of requiring the review of the 
submission prior to the meeting, thus pushing the review up in the 
queue. Therefore, we neither anticipate meeting with potential 
applicants to discuss pending submissions, nor would any such meeting 
fall within 512(b)(3) of the act or this rule.
    The proposed definition of presubmission conference limits 
presubmission conferences to conferences ``requested by the potential 
applicant.'' The act provides that any potential applicant is entitled 
to a presubmission conference. However, the act does not specify that 
requests for presubmission conferences may be initiated only by 
potential applicants. Thus, we are revising the definition of 
presubmission conference to remove this restriction. While, typically, 
potential applicants will initiate requests for meetings to discuss 
investigational or submission requirements, FDA may encourage potential 
applicants to request a presubmission conference if we believe such a 
meeting may facilitate the development of data to support approval.
    (Comment 3) One comment expresses concern that the binding nature 
of presubmission conferences results in a process that appears to be 
somewhat inflexible. The comment notes that a new animal drug (i.e., 
the formulation) or its proposed uses (i.e., the intended uses or 
conditions of use) may change as the product is developed and was 
concerned that data requirements may change in the time it takes FDA to 
draft and clear the presubmission conference agreement.
    (Response) The act requires that agreements reached in 
presubmission conferences be binding. However, the act also provides 
flexibility by allowing for changes to such agreements if FDA and the 
applicant or requester mutually agree to modify the requirement, or if 
FDA determines that a substantiated scientific requirement essential to 
the determination of safety or effectiveness of the animal drug 
involved appears after the conference. Thus, although the parties may 
agree to modify a presubmission conference agreement, FDA cannot 
unilaterally change the agreement unless there are valid scientific 
reasons for doing so.
    To ensure that investigational and submission requirements do not 
become outdated before a presubmission conference agreement is sent to 
a potential applicant, we are revising Sec.  514.5(f)(1) in the final 
regulation (as described in the following paragraphs) to add a 
timeframe in which we will send a copy of the memorandum of conference, 
which includes any presubmission conference agreement, to the potential 
applicant to review.
    (Comment 4) One comment requests that the regulations make it 
absolutely clear that the sponsor should be able to determine, with 
certainty, through a presubmission conference all the studies necessary 
to establish the human safety, animal safety, and efficacy of a new 
animal drug. Another comment expresses concern that the regulation 
describes a process that appears to be somewhat inflexible because, 
among other things, it requires us to establish investigational or 
submission requirements for new animal drugs that may change (e.g., in 
formulation, intended uses, and conditions of use) based on information 
gathered throughout their development.
    (Response) The act and this final regulation provide both certainty 
and flexibility in determining investigational or submission 
requirements. First, the act and the regulation specifically state that 
any person intending to file a NADA or a request for investigational 
exemption is entitled to one or more conferences in order to reach 
agreement on certain submission requirements (section 512(b)(3) of the 
act and Sec.  514.5(b)). Second, the act and the regulation specify 
that an agreement may be changed if the following conditions are met: 
(1) FDA and the applicant or requester mutually agree to modify the 
requirement or (2) FDA by written order determines that a substantiated 
scientific requirement essential to the determination of safety or 
effectiveness of the animal drug involved has appeared after the 
conference (section 512(b)(3) of the act and Sec.  514.5(g)). Thus, the 
presubmission conference process provides certainty absent unforeseen 
circumstances, but provides means to address contingencies that may 
arise during new animal drug development.
    The provision entitling a potential applicant to one or more 
presubmission conferences is intended to recognize that it may not be 
possible to establish

[[Page 51164]]

all of the investigational or submission requirements in one 
presubmission conference because the new animal drug or its proposed 
uses may change as it is being developed. The statute and regulation do 
not preclude the parties from reaching agreement regarding all the 
studies necessary to establish the human safety, animal safety, and 
effectiveness of a new animal drug in a single presubmission 
conference. However, we believe it is more likely that for most new 
animal drugs the parties will participate in a series of presubmission 
conferences.
    Potential applicants may choose to and are encouraged to request 
more than one presubmission conference. For example, if the outcome of 
one study required to satisfy one of the approval requirements is 
likely to affect the number or types of additional studies that would 
be needed to satisfy the same or a different approval requirement, or 
if it may affect the formulation or proposed uses of the new animal 
drug. By sequencing presubmission conferences, a potential applicant 
may be able to avoid conducting studies that will not support or be 
necessary for approval.
    Potential applicants should consider requesting presubmission 
conferences on specific, manageable issues and should include in the 
advance material to us all relevant information and data available to 
date. Potential applicants should also consider the sequencing of such 
conferences so that information and data on which future requirements 
may depend are available. For example, a potential applicant may 
request one presubmission conference to discuss the number and types of 
studies necessary to demonstrate safety and request another 
presubmission conference to discuss studies necessary to demonstrate 
effectiveness after they have conducted studies to demonstrate that a 
particular dose or dosage range is safe.

C. General (Sec.  514.5(a))

    We are renaming this section ``General Principle Underlying the 
Conduct of a Presubmission Conference.'' We are deleting the first two 
sentences of proposed Sec.  514.5(a). Although these sentences 
accurately reflect our view that a presubmission conference is the 
forum for a potential applicant and FDA to reach agreement regarding 
investigational or submission requirements and that the goal of such a 
conference is to enhance the animal drug development and evaluation 
process, these sentences do not set forth requirements or expectations 
and should not be included in the codified language.
    We are keeping the last sentence, but changing it to read as 
follows: ``The general principle underlying the conduct of any 
presubmission conference is that there should be candid, full, and open 
communication.'' We believe it is important that all participants to a 
presubmission conference, potential applicants and FDA representatives 
alike, understand that candid, full, and open communication is 
essential to ensuring that such conferences will enhance the animal 
drug development and evaluation process.

D. Requesting a Presubmission Conference (Sec.  514.5(b))

    We are revising the second sentence of proposed Sec.  514.5(b) to 
read more clearly: ``A potential applicant's request for a 
presubmission conference must be submitted to FDA in a signed letter.'' 
If an investigational new animal drug file has not been established 
prior to receiving a request for a presubmission conference, our 
general practice is to establish an investigational new animal drug 
file for administrative reasons such as recordkeeping and protecting 
the confidentiality of information submitted by potential applicants.

E. Advance Information (Sec.  514.5(d))

    We are revising proposed Sec.  514.5(d), among other things, to 
clarify what information is required to be submitted to FDA in advance 
of a presubmission conference. Proposed Sec.  514.5(d) specified that:
    The potential applicant must provide to FDA, at least 30 days 
before a scheduled presubmission conference, a copy of any materials 
to be presented at the conference, a list of proposed indications or 
a copy of the proposed labeling for the product under consideration, 
and any background material that provides an adequate scientific 
rationale to support the potential applicant's position on issues 
listed on the proposed agenda for the conference.
    Under Sec.  514.5(b), a potential applicant is required to provide 
a proposed agenda with their request for a presubmission conference. We 
are revising Sec.  514.5(d) to clarify that a potential applicant is 
required to submit a detailed agenda as part of the advance materials 
submitted to FDA at least 30 calendar days before the scheduled 
meeting. We expect that many potential applicants will schedule 
presubmission conferences more than 30 days before the date they want 
to meet with FDA so that they can increase the likelihood that the 
appropriate staff representing the potential applicant and FDA will be 
available to meet on a particular date or within a particular 
timeframe. If the agenda is drafted at the time the meeting is 
requested, the potential applicants may not be able to provide the 
detail and focus for each of the agenda items at the level that is 
needed for reviewers to prepare for the presubmission conference. The 
proposed agenda submitted at the time of the request should identify 
the general areas of discussion and provide enough information to allow 
us to evaluate who from FDA should attend the meeting. But, we also 
need a detailed agenda at least 30 days before the presubmission 
conference is scheduled so that attendees can prepare for a productive 
discussion of the issues.
    What constitutes a ``detailed agenda'' will depend on the purpose 
of the presubmission conference. The question the potential applicant 
should ask in preparing a detailed agenda is ``what information is 
necessary for a full and productive discussion on the issues identified 
in the agenda?'' Consistent with this revision, we are removing the 
word ``proposed'' that appears before agenda at the end of the first 
sentence in proposed Sec.  514.5(d).
    Proposed Sec.  514.5(d) also required the potential applicant to 
provide to FDA ``* * * a list of proposed indications or a copy of the 
proposed labeling for the product under consideration* * *.'' We are 
revising Sec.  514.5(d) to require submission of a list of proposed 
indications and also to require a copy of proposed labeling, if 
available.
    We encourage potential applicants to develop proposed labeling 
early in the drug development process. By proposed labeling we mean 
that textual portion of the label that describes, among other things, 
the new animal drug, dosage form, route of administration, and the 
intended uses and conditions of use for the new animal drug at a level 
of specificity appropriate to the stage of development. Because this 
wording often drives the submission or investigational requirements, 
proposed label would assist us in establishing appropriate 
requirements.
    Finally, we are adding the words ``a copy of'' and deleting the 
word ``adequate'' to clarify that a potential applicant is required to 
provide ``a copy of any background material that provides scientific 
rationale to support the applicant's position on issues listed in the 
agenda for the conference.'' We do not need originals of the background 
material. Readable copies may be provided in lieu of originals. The 
background material should provide a scientific rationale for the 
applicant's position on issues listed in the detailed agenda. We will 
determine after review

[[Page 51165]]

and discussion at the presubmission conference whether the materials 
provide ``adequate'' scientific rationale to support such positions.
    (Comment 5) One comment states that, based on their experience with 
FDA, if the amount of advance information requested in the proposed 
rule is provided, there may be little opportunity for dialog or need 
for the meeting because the agency will have made its decisions prior 
to the actual meeting. Two comments suggest rather than requiring all 
information to be submitted prior to the meeting, providing background 
materials to acquaint participants with information that will be 
discussed should be sufficient.
    (Response) The goal of a presubmission conference is to reach 
agreement regarding some or all of the investigational or submission 
requirements. If we are to be prepared for a meeting, and prepared to 
make binding decisions at such a meeting, sufficient scientific 
background materials must be provided in advance for our review and 
consideration. That does not mean that we will not be open to 
discussion. In fact, having the material in advance will allow our 
participants to prepare for a productive discussion because they will 
be able to formulate appropriate questions, conduct further research on 
issues, and apply their review experience, as appropriate.
    It should be easier for potential applicants to provide copies of 
all material they evaluated or referenced relating to an issue listed 
in the agenda, rather than selecting or summarizing relevant material. 
FDA participants should have the opportunity to review all 
documentation in order to exercise their scientific judgment and, in 
many cases, years of experience reviewing new animal drugs to determine 
what information is relevant. If potential applicants select what 
information is submitted or not submitted, FDA participants may not 
have all the materials needed to make the decision or to provide the 
best advice to the potential applicants regarding the least burdensome 
investigational or submission requirements that are likely to result in 
approval.
    (Comment 6) One comment believes there should be a mechanism for 
FDA to ask the applicant questions or request additional information 
via telephone call or e-mail, rather than delay the meeting. The 
comment hopes delays in holding a presubmission conference will be the 
exception, not the norm.
    (Response) Nothing in this rule prevents FDA staff from contacting 
a potential applicant to ask clarifying questions or to request minor 
(i.e., nonvoluminous, noncomplex) additional information. If questions 
can be answered and minor additional materials can be provided to us in 
a timely manner prior to the presubmission conference, there would be 
no need to postpone a meeting.
    The advance materials must permit a productive discussion of the 
issues, and if we are to reach a binding agreement with a potential 
applicant, sufficient information on which to make an informed 
decision. Whether and how often presubmission conferences are delayed 
will depend in part upon the quality and completeness of the advance 
materials submitted by the potential applicant.
    We are revising the last sentence in proposed Sec.  514.5(d) to 
clarify that: ``* * * FDA may elect to postpone part or all of the 
meeting until sufficient materials are provided to FDA.'' If sufficient 
materials are available to proceed with a productive discussion on some 
issues but not others, we intend to meet with the potential applicant 
to discuss those issues for which sufficient advance materials have 
been provided, if the issues are severable. Our goal is to assist 
potential applicants in moving forward with the development and 
approval of new animal drugs.

F. Conduct of a Presubmission Conference (Sec.  514.5(e))

    We are revising the last sentence of proposed Sec.  514.5(e) to 
clarify that: ``The submission or investigational requirement may 
include, among other things, the number, types, and general design of 
studies that are necessary to demonstrate the safety and effectiveness 
of a new animal drug.'' We are changing ``will'' to ``may'' because any 
particular submission or investigational requirement may include the 
number, types, general design, or some combination of these elements, 
of studies that are required to demonstrate safety and effectiveness, 
but not all of them. We are adding the phrase ``among other things'' 
because requirements may address issues other than number, type, or 
general design of studies, e.g., labeling requirements or methods 
validation. The first sentence of proposed Sec.  514.5(a) stated that 
presubmission conferences provide a forum to discuss the objectives and 
general design of particular studies. Because we are deleting that 
sentence in the final rule, we are clarifying in final Sec.  514.5(e) 
that submission or investigational requirements may include the general 
design of the studies.

G. Documentation of a Presubmission Conference (Sec.  514.5(f))

    We are revising the first sentence in proposed Sec.  514.5(f)(1) to 
clarify the contents of the memorandum of conference. ``FDA will 
prepare a memorandum for each presubmission conference that will 
include, among other things: any background information pertinent to 
the request for the meeting; a summary of the key points of discussion; 
agreements; and action items and assignments of responsibility.'' Other 
changes to Sec.  514.5(f)(1) are described in the responses to comments 
that follow. Further, we are dividing final Sec.  514.5(f)(1) into 
paragraphs to improve clarity and readability.
    (Comment 7) One comment seems concerned that the presubmission 
conference agreement is part of the memorandum of conference. Further, 
the comment suggests that it may be more expeditious and timely for the 
registrant to prepare the memorandum of understanding with subsequent 
approval by the agency.
    (Response) We note that the comment uses the term ``memorandum of 
understanding.'' Neither FDA nor potential applicants draft memorandum 
of understanding to document presubmission conferences. As defined in 
FDA's Staff Manual Guide 2830.1, the term ``Memoranda of 
Understanding'' is primarily used by FDA to refer to formal agreements 
between FDA and other Government (Federal, State, or local) agencies. 
We assume that the comment meant ``memorandum of conference.''
    As discussed in the proposed rule, that portion of the memorandum 
of conference that documents any agreements reached regarding all or 
part of a submission or investigational requirement will be included 
under the heading ``Presubmission Conference Agreement'' (65 FR 51782 
at 51783). We believe it is more efficient for us to prepare the 
memorandum of conference and that it is important to provide the 
agreement in the context of the information and discussions that took 
place during the presubmission conference.
    We are revising the sentence in proposed Sec.  514.5(f)(1) that 
read: ``If a memorandum is silent on an issue, * * * such silence 
cannot be construed as agreement between FDA and the potential 
applicant on the issue'' to clarify that it is specifically the 
presubmission conference agreement section of the memorandum in which 
silence does not constitute agreement.

[[Page 51166]]

 This sentence logically follows the sentence explaining that the 
presubmission conference agreement is a section of the memorandum and 
will read as follows: ``If the presubmission conference agreement 
section of the memorandum is silent on an issue, including one that was 
discussed in the conference or addressed by materials provided for the 
conference, such silence does not constitute agreement between FDA and 
the potential applicant on the issue.''
    (Comment 8) The preamble to the proposed rule states that 
presubmission conference agreements would generally include timeframes 
for completion. One comment acknowledges that scientific knowledge on 
which agreements are based may change over long periods of time, but 
expresses concern that no guidance on the duration of those timeframes 
was given.
    (Response) Presubmission conference agreements will be based on 
scientific knowledge available at the time of the agreement. The 
inclusion of timeframes in a presubmission conference agreement is 
intended, as the comment notes, to recognize that the state of 
scientific knowledge may change over time. The inclusion of a timeframe 
signals to a potential applicant or us the need to revisit whether the 
submission or investigational requirements are still relevant after 
that time.
    What constitutes a reasonable timeframe will vary significantly 
depending on, among other things, the nature of the product, the 
species for which the drug is intended, and the proposed uses. For 
example, time may affect the inferential value of data. Time-dependent 
factors include, e.g., genetics of the target animal and the target 
organism, husbandry practices, and diets (62 FR 59830 at 59833, 
November 5, 1997).
    Timeframes and any other caveats should be discussed as part of the 
process of reaching agreement. Examples of other caveats that might be 
included in a presubmission conference agreement include specification 
of the formulation (e.g., final formulation) on which the studies 
should be conducted and timeframes for updating literature searches.
    (Comment 9) All of the comments express concern that the proposed 
regulation does not include a timeframe in which FDA would issue the 
memorandum of conference, and thus, the presubmission conference 
agreement, if one is reached. Most comments suggest that FDA should be 
required to provide the memorandum of conference to the potential 
applicant within 25 days of the conference. They state that this 
timeframe is consistent with the timeframe in which FDA must provide 
written justification if it is requiring more than one field study to 
provide substantial evidence of effectiveness. One comment is 
specifically concerned that in the time it takes for the agreement to 
clear the agency, the submission or investigational requirements might 
change.
    (Response) We agree that FDA should provide the memorandum of 
conference to the potential applicant in a timely manner and will 
provide the memorandum no later than 45 days after the date of the 
presubmission conference. Accordingly, we are revising the sentence in 
proposed Sec.  514.5(f)(1) that read: ``FDA will provide a copy of the 
memorandum to the potential applicant for review'' to read: ``FDA will 
send a copy of the memorandum to the potential applicant for review no 
later than 45 calendar days after the date of the conference.''
    We cannot provide the memorandum in 25 days because it is not a 
practical timeframe for issuing most memoranda of conference 
considering all of our other review responsibilities. Further, we 
expect that many agreements will relate to investigational or 
submission requirements other than those that relate to effectiveness 
and will not include a requirement for more than one field study. If we 
require more than one field study to provide substantial evidence of 
effectiveness, we will provide our justification for that requirement 
no later than 25 calendar days after the date of the conference as 
required by section 512(b)(3) of the act and as described in Sec.  
514.5(f)(2).
    We are also revising the fourth sentence of proposed Sec.  
514.5(f)(1) to clarify that as follows: ``The potential applicant will 
have 30 calendar days from the date a copy of the memorandum of 
conference is sent to the applicant to request changes to, or 
clarification of, the substance of the memorandum.'' For purposes of 
calculating the timeframe for the potential applicant to respond, the 
only date of record from which we can calculate the time is the date 
the memorandum is sent. This sentence will follow the sentence that 
discusses that silence of a presubmission conference agreement on an 
issue does not constitute agreement.
    We are removing the sentence in proposed Sec.  514.5(f)(1) 
regarding calculation of the timeframe because this is an 
administrative matter and need not be addressed by regulation.
    (Comment 10) Two comments note that the potential applicant is 
given 30 days to request changes to or seek clarification of FDA's 
memorandum of conference, but no timeframe is given in which FDA must 
respond to the potential applicant's request. One comment proposed that 
FDA respond within 25 days, another proposed 15 days.
    (Response) We will send a response to the potential applicant's 
request for changes to or clarification of a memorandum of conference 
no later than 45 calendar days after the date such request is received. 
If we agree that the memorandum of conference needs to be changed to 
correct or clarify content, we will prepare an amended memorandum of 
conference and include a copy of the amended memorandum as part of our 
response to the potential applicant.
    In the final rule, Sec.  514.5(f)(1)(iii) will include a timeframe 
for FDA to send a response to a potential applicant's request for 
changes or clarification, and clarify the administrative steps relating 
to requesting and documenting changes to the presubmission conference 
agreement. Accordingly, the last three sentences of final Sec.  
514.5(f)(1) will read: ``If a potential applicant requests changes or 
clarification, the request must be sent to FDA. If the potential 
applicant requests changes or clarification, FDA will send the 
potential applicant a response to their request no later than 45 
calendar days after the date of receipt of the request.'' The last 
sentence of Sec.  514.5(f)(1)(iv), under the paragraph ``Administrative 
record,'' will read: ``A copy of FDA's original memorandum of 
conference and, as appropriate, a copy of an amended memorandum to 
correct or clarify the content of the original memorandum will be made 
part of the administrative file.''
    We hope to minimize the need for changes to or clarification of the 
memorandum by summarizing at the close of each presubmission conference 
the key points of discussion, agreements, and action items, and the 
assignments of responsibilities for each of those items. That summary 
of key points will provide the potential applicant with the first and 
best opportunity to ensure that the discussions and any agreements 
reached will be accurately documented in the memorandum of conference. 
If the potential applicant disagrees with the summary presented at the 
end of the presubmission conference, the potential applicant should 
discuss the disagreement with us before the close of the presubmission 
conference. In the event the potential applicant finds, after reviewing 
FDA's memorandum of

[[Page 51167]]

conference, that correction to or clarification of the memorandum is 
needed, the potential applicant should request changes to or 
clarification of the memorandum by submitting a letter. Following the 
presubmission conference, FDA will only review a request for changes to 
or clarification of the memorandum that is submitted within 30 calendar 
days from the date a copy of the memorandum is sent to the applicant. 
The potential applicant should not request changes to or clarification 
of the memorandum of conference by submitting the potential applicant's 
version of the memorandum.
    (Comment 11) The act, as amended by the ADAA, requires that FDA 
justify a requirement for more than one field study to provide 
substantial evidence of effectiveness. Two comments assert that FDA is 
attempting to circumvent the intent of the ADAA by indicating that it 
may require a single study in multiple locations.
    The comments assert that the issue of whether a field study 
conducted at multiple sites using a single protocol is a single study 
or represents more than one study has long been an area of disagreement 
between industry and FDA. But, one comment acknowledges it may be true 
that, for some small animal clinical studies, multiple locations may be 
necessary to obtain sufficient numbers of patients.
    (Response) FDA is not attempting to circumvent the intent of the 
ADAA. Whether a study conducted at multiple sites following the same 
protocol is most appropriately considered a single study or multiple 
studies depends upon the degree of coordination between the sites, the 
intent of the analysis, whether the data would be pooled to assess 
statistical significance, and the generalizability of the findings 
(inferential space). Although ADAA does not require FDA to provide 
justification for a multilocation field study, FDA has agreed that in 
the spirit of ADAA it will provide justification of the need for a 
multilocation field study (substantial evidence final rule at 64 FR 
40746 at 40750, July 28, 1999). To that end, proposed Sec.  514.5(f)(2) 
provided: ``If FDA requires one field study to be conducted at multiple 
locations, FDA will, at the request of the potential applicant, provide 
written or verbal justification for requiring multiple locations'' (64 
FR 51786).
    If we require more than one field study, we will provide written 
justification within 25 days of a conference why more than one field 
study is essential to demonstrate by substantial evidence that the new 
animal drug is effective. After further consideration FDA has decided 
that if we require one field study with multiple locations, we will 
provide both verbal justification for why more than one location is 
required during the presubmission conference and written justification 
as part of the memorandum of conference, which must be provided in 
accordance with this final rule no later than 45 days after the date of 
the conference. We are revising the last sentence of proposed Sec.  
514.5(f)(2) to clarify when and how we will provide justification for 
requiring multiple locations: ``If FDA requires one field study to be 
conducted at multiple locations, FDA will provide justification for 
requiring multiple locations verbally during the presubmission 
conference and in writing as part of the Memorandum of Conference.''
    The principles governing the number and types of studies necessary 
to demonstrate by substantial evidence that a new animal drug is 
effective are addressed in Sec.  514.4(b)(3) and, extensively, in the 
preambles to the proposed and final rules (62 FR 59830 and 64 FR 
40746). The preambles to the proposed and final substantial evidence 
rule (62 FR 59830 at 59833 and 64 FR 40746 at 40749) further describe 
the considerations for designing a single adequate and well-controlled 
study that may demonstrate substantial evidence of effectiveness. A 
single multilocation study may be an accepted way of evaluating drugs 
efficiently if it is designed to provide independent substantiation and 
inferential value. In any instance, presubmission conferences give 
potential applicants a venue to discuss, among other things, the least 
burdensome requirements for demonstrating effectiveness.

H. Modification of Presubmission Conference Agreements (Sec.  514.5(g))

    (Comment 12) One comment states that the Federal Register document 
for the proposed rule left Sec. Sec.  514.4 or 514.5 open for future 
language that would specify how the presubmission conference agreement 
could be modified.
    (Response) In both the proposed and final rule, the bases for 
modifying a presubmission conference are found in Sec.  514.5(g). The 
preamble to the proposed rule stated that proposed Sec.  514.4 
describes procedures for requesting, conducting, and documenting a 
presubmission conference. These procedures were proposed, however, to 
be codified at Sec.  514.5, not in Sec.  514.4 of the proposed rule. In 
the final rule, these procedures are codified at Sec.  514.5. Existing 
Sec.  514.4 further defines substantial evidence.

I. When the Terms of a Presubmission Conference Agreement Are No Longer 
Binding (Sec.  514.5(h))

    (Comment 13) Two comments believe the provisions in proposed Sec.  
514.5(h), when the terms of a presubmission conference are no longer 
binding, are outside the statutory authority of the agency. The act, as 
amended by the ADAA, provides that agreements regarding submission or 
investigation requirements reached at a presubmission conference shall 
bind the Secretary of Health and Human Services (the Secretary) and the 
applicant or requester except in two specific situations. The first is 
by agreement of both parties, and the second is where the Secretary, by 
written order, determines that a substantiated scientific requirement, 
essential to the determination of safety or effectiveness of the animal 
drug involved, has appeared after the conference. The comments assert 
that the agency does not have the authority to create other mechanisms 
by which FDA can unilaterally declare presubmission conference 
agreements not binding.
    (Response) We are revising the heading in proposed Sec.  514.5(h), 
``When the terms of a presubmission conference agreement are no longer 
binding'' to ``When the terms of a presubmission conference agreement 
are not valid.'' The heading in the proposed regulation did not 
accurately reflect the content or intent of the provision.
    The intent of proposed Sec.  514.5(h) was not to describe 
additional conditions under which a presubmission conference agreement 
is no longer binding. The intent of the provision was to emphasize that 
if presubmission conference agreements are to be meaningful and valid, 
they must be based on the truthful submission of information and must 
bind both parties. There cannot be agreement between parties if 
statements or representations made by one party are materially false, 
fictitious, or fraudulent. Thus, FDA considers agreements based on 
untrue statements or mispresentations of material facts to never have 
been valid. Further, if a party fails to follow any material term of 
the agreement, such agreements may become invalid.
    We disagree with the comments that assert that the provisions in 
proposed Sec.  514.5(h) are outside the statutory authority of the 
agency. As stated by one comment, no one should be untruthful or 
mislead the agency. In fact it is a crime to knowingly and willfully 
make an untruthful statement to FDA on matter within its jurisdiction; 
specifically, 18 U.S.C. 1001(a) provides:

[[Page 51168]]

    Except as otherwise provided in this section, whoever, in any 
matter within the jurisdiction of the executive, legislative, or 
judicial branch of the Government of the United Stated, knowingly 
and willfully--
    (1) falsifies, conceals, or covers up by any trick, scheme, or 
device a material fact;
    (2) makes any materially false, fictitious, or fraudulent 
statement or representation; or
    (3) makes or uses any false writing or document knowing the same 
to contain any materially false, fictitious, or fraudulent statement 
or entry;
    shall be fined under this title or imprisoned not more than 5 
years, or both.
    The ADAA does not limit or in any way affect the applicability of 
the criminal code to potential applicants who provide materially false, 
fictitious, or fraudulent information to FDA in the course of providing 
information to facilitate the conduct of a presubmission conference or 
to support new animal drug approval.
    Further, section 701(a) of the act (21 U.S.C. 371(a)) vests in the 
Secretary the authority to issue regulations for the efficient 
enforcement of the act. No provision of the ADAA limits or supersedes 
the authority granted to the Secretary, and FDA by delegation, under 
section 701(a) of the act. FDA has the authority to make clear the 
conditions under which agreements were never valid or are no longer 
valid.
    (Comment 14) Two comments are concerned by the provision in the 
proposed rule that stated: ``[a] presubmission conference agreement 
will no longer be binding * * * if the potential applicant fails to 
follow any term of the agreement.'' Both comments believe that it would 
be inequitable for an entire agreement to be voided if the applicant 
failed to comply with some nonmaterial portion of the agreement. One 
comment suggests that each component of the presubmission conference 
agreement should be judged upon its own merits and that failure to meet 
one provision of the agreement should not automatically invalidate the 
whole agreement. The other comment is particularly concerned that 
failure to meet timeframes provided for in presubmission conference 
agreements may frequently cause agreements to be invalidated.
    (Response) We do not intend to invalidate an entire presubmission 
conference agreement if the potential applicant fails to follow 
immaterial term(s) of the agreement and the term(s) of the 
presubmission conference agreement are severable. Thus, we are adding 
``material'' before the word term in Sec.  514.5(h)(1)(ii). We intend 
to examine the severability of the terms of a presubmission conference 
agreement on a case-by-case basis.
    For example, a determination of whether a timeframe is a material 
term of the agreement will be made by FDA on a case-by-case basis. We 
understand the comment's concern that timeframes included as terms of 
the presubmission conference agreement may result in invalidation of 
the presubmission conference agreement. However, we believe that steps 
have been built into the presubmission conference process to decrease 
the likelihood that timeframes will present a major obstacle to 
complying with the terms of the agreement. First, the potential 
applicant and FDA should discuss and agree to reasonable timeframes 
during the presubmission conference. Second, we have added timeframes 
for FDA to provide the memorandum, including the presubmission 
conference agreement, and our response to any requests for correction 
or clarification to ensure our timely response to potential applicants. 
Finally, we anticipate that the recent enactment of the Animal Drug 
User Fee Act of 2003 will minimize any significant delays that occur 
within FDA in reviewing submissions that may affect the potential 
applicant's ability to meet reasonable timeframes in the agreement.

III. Environmental Impact

    This final rule clarifies the procedures for requesting, 
conducting, and documenting presubmission conferences. We have 
carefully considered the potential environmental impacts of this rule 
and determined that this action is of a type, as described in 21 CFR 
25.30(h), that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

IV. Analysis of Impacts

    We have examined the impacts of this final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages, distributive impacts and equity). We believe that this 
final rule is consistent with the regulatory philosophy and principles 
identified in Executive Order 12866. We have also determined that the 
rule is not a significant regulatory action as defined by the Executive 
order and, therefore, is not subject to review under the Executive 
order. Under the Regulatory Flexibility Act, if a regulation has a 
significant economic impact on a substantial number of small entities, 
the agency must analyze regulatory options that would minimize the 
impact on small entities. FDA certifies in accordance with the 
Regulatory Flexibility Act (5 U.S.C. 601-612) that this rule will not 
have a significant economic impact on a substantial number of small 
entities, and therefore, a regulatory flexibility analysis is not 
required.
    Under section 512(b)(3) of the act, as amended by the ADAA, any 
person intending to file an NADA or supplemental NADA or to investigate 
a new animal drug is entitled to one or more conferences prior to such 
submission to reach an agreement establishing a submission or 
investigational requirement. The purpose of presubmission conferences 
is to allow a potential applicant and FDA to reach agreement regarding 
a submission or investigational requirement, including the number and 
types of studies that are necessary to demonstrate that the new animal 
drug is safe and effective for its intended uses.
    Prior to the enactment of the ADAA, CVM had already been 
encouraging sponsors of NADAs to participate in conferences with FDA to 
discuss in detail what studies are necessary to demonstrate the safety 
and effectiveness of the particular new animal drug being investigated. 
We found that, as a result of this direct communication during the 
development and review of new animal drugs, both the drug development 
and review processes became more efficient. This final rule implements 
the statutory entitlement to a presubmission conference, and thus, it 
will ensure that this benefit will continue where potential applicants 
request a presubmission requirement.
    FDA is not able to make a precise estimate of the savings that 
industry has realized through presubmission conferences, or of any 
increase in the number of presubmission conferences that may be 
requested as a result of the statutory entitlement. This final rule 
describes the procedures for requesting, conducting, and documenting 
presubmission conferences and secures an avenue of communication 
between us and the potential applicants through which both can agree on 
the studies needed for a certain drug, thereby reducing unnecessary 
studies and review periods.

[[Page 51169]]

    In the proposed rule, we forecasted a range of savings that may be 
expected from any decrease in approval time resulting from a potential 
applicant requesting a presubmission conference. We estimated a 
straight-line increase of a prospective drug's sales revenues from the 
application's approval up to $5 million in the 10th year and then 
deceasing again to zero in the 20th year. Because many new animal drugs 
attain sales much greater than $5 million, we estimated results in a 
rather conservative benefit. Assuming pretax profit of 20 percent of 
sales revenue, we estimated the present value of the profits from a 1- 
to 6-month decrease in approval time at $20,000 to $120,000 using a 7 
percent discount rate. Research costs saved by the firm from not 
conducting unnecessary studies would be added to this amount. 
Regardless of the exact reduction in the drug review period, potential 
applicants would only be expected to request a presubmission conference 
if they expected the net benefit of the conference to be positive. We 
also concluded that the proposed rule would not impose any mandatory 
compliance costs.
    We did not receive any comments that challenged our conclusions 
concerning the benefits or costs of the proposed rule. Further, the 
modifications made to this final rule would not lead us to change our 
conclusions concerning the aforementioned costs and benefits of the 
rule.
    Section 202(a) of the Unfunded Mandates Reform Act requires that 
agencies prepare a written statement of anticipated costs and benefits 
before proposing any regulation that may result in an expenditure by 
State, local and tribal governments in the aggregate, or by the private 
sector, of $100 million or more (adjusted annually for inflation) in 
any one year. The Unfunded Mandates Reform Act does not require FDA to 
prepare a statement of costs and benefits for this final rule because 
the rule is not expected to result in any 1-year expenditure that would 
exceed $100 million adjusted for inflation. The current inflation-
adjusted statutory threshold is approximately $110 million.

V. Federalism

    We have analyzed this final rule in accordance with the principles 
in Executive Order 13132. We have determined that the final rule does 
not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, we have concluded that the 
final rule does not contain policies that have federalism implications 
as defined in the order and, consequently, a federalism summary impact 
statement has not been prepared.

VI. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title, 
description, and respondent description of the information collection 
provisions are shown in the following paragraphs with an estimate of 
the annual reporting burden. Included in the estimate is the time for 
reviewing instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    Title: Presubmission Conferences
    Description: This final rule is intended to implement section 
512(b)(3) of the act which entitles any person intending to file an 
NADA or supplemental NADA or to investigate a new animal drug to 
request one or more conferences with FDA to reach an agreement 
establishing a submission or investigational requirement. Prior to the 
enactment of the section 512(b)(3) of the act, we encouraged sponsors 
to meet with FDA to discuss the number and types of studies necessary 
to demonstrate that a new animal drug is safe and effective. We found 
that these meetings increased the efficiency of the drug development 
and drug review processes. We are publishing this final rule to 
describe how to request, conduct, and document a presubmission 
conference.
    Final Sec.  514.5(b) describes the information that must be 
included in a letter submitted by a potential applicant requesting a 
presubmission conference, including a proposed agenda and a list of 
expected participants. Final Sec.  514.5(d) lists the information that 
must be provided by the potential applicant to FDA at least 30 days 
prior to a presubmission conference. This information includes a 
detailed agenda, a copy of any materials to be presented at the 
conference, a list of proposed indications and, if available, a copy of 
the proposed labeling for the product under consideration, and a copy 
of any background material that provides scientific rationale to 
support the potential applicant's position on issues listed in the 
agenda for the conference. Final Sec.  514.5(f) discusses the content 
of the memorandum of conference that will be prepared by FDA and gives 
the potential applicant an opportunity to seek correction to or 
clarification of the memorandum.
    Description of Respondents: Potential applicants

                                   Table 1.--Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
                         No. of        Annual frequency     Total annual        Hours per
      21 CFR          respondents        per response        responses           response         Total hours
----------------------------------------------------------------------------------------------------------------
514.4(b)                         190                  1                190                  7              1,330
----------------------------------------------------------------------------------------------------------------
514.4(d)                         190                  1                190                123             23,370
----------------------------------------------------------------------------------------------------------------
514.4(f)                         190                  1                190                 16              3,040
----------------------------------------------------------------------------------------------------------------
Total Hours                                                                                               27,740
----------------------------------------------------------------------------------------------------------------
There are no capital costs or operating and maintenance costs associated with this collection of information.

    Table 1 of this document provides, by relevant section, the 
estimated burden of requesting, preparing for, and participating in 
presubmission conferences. The numbers in the chart are based on 
consultation with several of the major research and development firms 
that are responsible for the development of new animal drugs. While we 
estimate that the final regulation will increase the annual paperwork 
burden associated with the

[[Page 51170]]

submission of NADAs, supplemental NADAs, and abbreviated NADAs, and 
requests for guidance on investigational requirements, we believe this 
increase will be offset by the resulting efficiencies (e.g., 
eliminating the conduct of studies that are not needed to support 
approval, decreasing requests from reviewers for additional or 
clarifying information during the review process).
    The information collection provisions of this final rule have been 
submitted to OMB for review.
    Prior to the effective date of this final rule, FDA will publish a 
notice in the Federal Register announcing OMB's decision to approve, 
modify, or disapprove the information collection provisions in this 
final rule. An agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB control number.

List of Subjects in 21 CFR Part 514

    Administrative practice and procedure, Animal drugs, Confidential 
business information, Reporting and recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs and 
redelegated to the Center for Veterinary Medicine, 21 CFR part 514 is 
amended as follows:

PART 514--NEW ANIMAL DRUG APPLICATIONS

0
1. The authority citation for 21 CFR part 514 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 360b, 371, 379e, 
381.

0
2. Section 514.3 is amended by adding the following definitions in 
alphabetical order:


Sec.  514.3  Definitions.

* * * * *
    Potential applicant means any person:
    (1) Intending to investigate a new animal drug under section 512(j) 
of the Federal Food, Drug, and Cosmetic Act (the act),
    (2) Investigating a new animal drug under section 512(j) of the 
act,
    (3) Intending to file a new animal drug application (NADA) or 
supplemental NADA under section 512(b)(1) of the act, or
    (4) Intending to file an abbreviated new animal drug application 
(ANADA) under section 512(b)(2) of the act.
    Presubmission conference means one or more conferences between a 
potential applicant and FDA to reach a binding agreement establishing a 
submission or investigational requirement.
    Presubmission conference agreement means that section of the 
memorandum of conference headed ``Presubmission Conference Agreement'' 
that records any agreement on the submission or investigational 
requirement reached by a potential applicant and FDA during the 
presubmission conference.
* * * * *

0
3. Section 514.5 is added to subpart A to read as follows:


Sec.  514.5  Presubmission conferences.

    (a) General principle underlying the conduct of a presubmission 
conference. The general principle underlying the conduct of any 
presubmission conference is that there should be candid, full, and open 
communication.
    (b) Requesting a presubmission conference. A potential applicant is 
entitled to one or more conferences prior to the submission of an NADA, 
supplemental NADA, or an ANADA to reach an agreement establishing part 
or all of a submission or investigational requirement. A potential 
applicant's request for a presubmission conference must be submitted to 
FDA in a signed letter. The letter must include a proposed agenda that 
clearly outlines the scope, purpose, and objectives of the 
presubmission conference and must list the names and positions of the 
representatives who are expected to attend the presubmission conference 
on behalf of the applicant.
    (c) Timing. A potential applicant may request one or more 
presubmission conferences at any time prior to the filing of a NADA, 
supplemental NADA, or an ANADA. A request for a presubmission 
conference must be received by FDA at least 30 calendar days in advance 
of the requested conference date. FDA will schedule the presubmission 
conference at a time agreeable to both FDA and the potential applicant.
    (d) Advance information. The potential applicant must provide to 
FDA, at least 30 calendar days before a scheduled presubmission 
conference, a detailed agenda, a copy of any materials to be presented 
at the conference, a list of proposed indications and, if available, a 
copy of the proposed labeling for the product under consideration, and 
copies of materials evaluated or referenced relative to issues listed 
in the agenda for the conference. If the materials are not provided or 
are not sufficient to provide the basis for meaningful discussion, FDA 
may elect to postpone part or all of the meeting until sufficient 
materials are provided to FDA.
    (e) Conduct of a presubmission conference. The potential applicant 
and FDA may each bring consultants to the presubmission conference. The 
presubmission conference(s) will be directed primarily at establishing 
agreement between FDA and the potential applicant regarding a 
submission or investigational requirement. The submission or 
investigational requirement may include, among other things, the 
number, types, and general design of studies that are necessary to 
demonstrate the safety and effectiveness of a new animal drug for the 
intended uses and conditions of use prescribed, recommended, or 
suggested in the proposed labeling for the new animal drug.
    (f) Documentation of a presubmission conference--(1) Memorandum of 
conference--(i) Preparation. FDA will prepare a memorandum for each 
presubmission conference that will include, among other things, any 
background pertinent to the request for meeting; a summary of the key 
points of discussion; agreements; and action items and assignments of 
responsibility. That portion of the memorandum of conference that 
documents any agreements reached regarding all or part of a submission 
or investigational requirement will be included under the heading 
``Presubmission Conference Agreement.'' If the presubmission conference 
agreement section of the memorandum is silent on an issue, including 
one that was discussed in the conference or addressed by materials 
provided for the conference, such silence does not constitute agreement 
between FDA and the potential applicant on the issue.
    (ii) Sending a copy to the potential applicant. FDA will send a 
copy of the memorandum to the potential applicant for review no later 
than 45 calendar days after the date of the conference
    (iii) Requests for changes or clarification. If a potential 
applicant requests changes to, or clarification of, the substance of 
the memorandum, the request must be sent to FDA within 30 calendar days 
from the date a copy of the memorandum is sent to the applicant. If the 
potential applicant requests changes or clarification, FDA will send 
the potential applicant a response to their request no later than 45 
calendar days after the date of receipt of the request.
    (iv) Administrative record. A copy of FDA's original memorandum of 
conference and, as appropriate, a copy of an amended memorandum to 
correct or clarify the content of the original

[[Page 51171]]

memorandum will be made part of the administrative file.
    (2) Field studies. If FDA requires more than one field study to 
establish by substantial evidence that the new animal drug is effective 
for its intended uses under the conditions of use prescribed, 
recommended, or suggested in the proposed labeling, FDA will provide 
written scientific justification for requiring more than one field 
study. Such justification must be provided no later than 25 calendar 
days after the date of the conference at which the requirement for more 
than one field study is established. If FDA does not believe more than 
one field study is required but the potential applicant voluntarily 
proposes to conduct more than one field study, FDA will not provide 
such written justification. If FDA requires one field study to be 
conducted at multiple locations, FDA will provide justification for 
requiring multiple locations verbally during the presubmission 
conference and in writing as part of the memorandum of conference.
    (g) Modification of presubmission conference agreements. An 
agreement made under a presubmission conference requested under section 
512(b)(3) of the act and documented in a memorandum of conference is 
binding on the potential applicant and FDA and may only be modified if:
    (1) FDA and the potential applicant mutually agree to modify, in 
part or in whole, the agreement and such modification is documented and 
provided to the potential applicant as described in paragraph (f)(1) of 
this section; or
    (2) FDA by written order determines that a substantiated scientific 
requirement essential to the determination of safety or effectiveness 
of the new animal drug appeared after the conference.
    (h) When the terms of a presubmission conference agreement are not 
valid--(1) A presubmission conference agreement will no longer be valid 
if:
    (i) The potential applicant makes to FDA, before, during, or after 
the presubmission conference, any untrue statement of material fact; or
    (ii) The potential applicant fails to follow any material term of 
the agreement; and
    (2) A presubmission conference may no longer be valid if the 
potential applicant submits false or misleading data relating to a new 
animal drug to FDA.
    (i) Dispute resolution. FDA is committed to resolving differences 
between a potential applicant and FDA reviewing divisions with respect 
to requirements for the investigation of new animal drugs and for 
NADAs, supplemental NADAs, and ANADAs as quickly and amicably as 
possible through a cooperative exchange of information and views. When 
administrative or procedural disputes arise, a potential applicant 
should first attempt to resolve the matter within the appropriate 
review division beginning with the individual(s) most directly assigned 
to the review of the application or investigational exemption. If the 
dispute cannot be resolved after such attempts, the dispute shall be 
evaluated and administered in accordance with applicable regulations 
(21 CFR 10.75). Dispute resolution procedures may be further explained 
by guidance available from the Center for Veterinary Medicine.

    Dated: August 10, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-18846 Filed 8-17-04; 8:45 am]

BILLING CODE 4160-01-S